Systematic exploration of eczema‐associated paediatric diseases in a Chinese population of millions: A retrospective observation study

Abstract Background Eczema is the most common form of dermatitis and also the starting point of atopic march. Although many eczema‐associated allergic and immunologic disorders have been studied, there remains a gap in the systematic quantitative knowledge regarding the relationships between all childhood disorders and eczema. This study aimed to systematically explore eczema‐associated childhood diseases using a real‐world, long‐term clinical dataset generated from millions of children in China. Methods Data were collected at 8,907,735 outpatient healthcare visits from 2,592,147 children between January 1, 2013, and August 15, 2019, at the largest comprehensive pediatric medical center in Zhejiang Province of China. The period prevalence differences in various pediatric diseases between children with and without eczema were used to test the independence of various pediatric disorders and eczema using Fisher's exact test. Bonferroni correction was used to adjust the p value in multiple testing. Odds ratio >2 with 95% confidence interval not including 1 and adjusted p < 0.05 was used to identify eczema‐associated diseases. Results Overall, 234 pediatric disorders were identified from more than 6000 different pediatric disorders. An interactive eczema‐associated disease map that has related quantitative epidemiological features called ADmap was published at http://pedmap.nbscn.org/admap. Thirty‐six of these disease associations have not been reported in previous studies. Conclusion This systematic exploratory study confirmed the associations of many well‐known diseases with eczema in Chinese children and also identified some novel and interesting associations. These results are valuable for the development of a comprehensive approach to the management of eczema in childhood.


| INTRODUCTION
Eczema is the most common form of dermatitis, affecting 245 million people globally in 2015, mostly children and adolescents. 1 Atopic dermatitis (AD), which is the most common type of eczema, has a wide range incidence among different countries and periods of observation. 2,3 In the United States, eczema affects approximately 10%-30% of people. 4 In China, the prevalence of AD among children aged 1-7 years is 12.94%. 5 A systematic review showed that the incidence and prevalence of eczema have increased globally. 6,7 The association between eczema and other diseases has been known for a long time. 8 Genetic and environmental factors are thought to play a role in the pathogenesis of eczema. 9 Approximately 50% of patients with severe AD will develop asthma, and 75% will develop allergic rhinitis. 10 People with eczema may also be particularly susceptible to bacterial, viral, and fungal skin infections. 11 Many other associated diseases have also been reported, such as conjunctivitis, 12 eosinophilic oesophagitis (EOE), 13 anemia, 14 cardiovascular diseases, 15 and psychosocial diseases. 16 To date, most studies have focused on several predefined diseases with relatively high prevalence rates. Most of these association studies were conducted in Western countries. We observed some potential associations in a previous study exploring relationships among common paediatric disorders using clinical data. 17 In this study, we systematically explored eczema-associated paediatric disorders using longer, larger, real-world clinical data generated from a children's hospital in China.

| Statistical analyses
Among these 2,592,147 paediatric patients, 91,515 children had been diagnosed with eczema at least once. In all these diagnoses of eczema, 91.1% were made by dermatologists, 2.9% by pediatricians, and the rest by various specialties such as ophthalmologists, ophthalmologists, urologists, and allergists. The incidences of different disorders in children with/without eczema were calculated. As for many disorders with relatively low prevalence, Fisher's exact tests were used to determine whether there were nonrandom associations between the disease and eczema. For each paediatric disorder, 6881 disease eczema pairs were tested based on the children's disease and eczema status. Bonferroni correction was used to adjust the p value in multiple testing.
Diseases positively associated with eczema (positive diseases) were defined by the following criteria: odds ratio (OR) >2, 95% confidence interval (CI) not including 1, adjusted p value of Fisher's exact test <0.05, and a visiting rate among eczema patients (the number of patients with eczema and visit for this specific diseases/ the total number of patients with eczema) > 0.0001 to ensure that each subset was large enough to achieve sufficient statistical power to detect a difference between patients with and without eczema. All statistics and calculations were performed in the R (v3.4.0) environment. The mean and standard deviation of age of the positive diseases in the group with and without eczema were also calculated. The novelty of associations was determined by a literature search in the PubMed database.
Many rare diseases with a prevalence of less than 1 in 10,000 people have also been reported to have an eczema phenotype. We also explored rare eczema-associated diseases using RDmap, 18 which is a novel rare disease knowledge base developed by our group that can identify rare diseases based on standard phenotype terms. Four phenotypes (HP:0000964 eczema; HP:0000976 eczematoid dermatitis; HP:0001047 AD; and HP:0011127 perioral eczema) were used to search for rare diseases in the RDmap. The rare diseases with an age of onset in the antenatal, neonatal and childhood were included.

| Patient and public involvement
Patient and public were not involved in any way in this study.

| RESULTS
Among more than 6000 paediatric disorders, 234 diseases were identified as being potentially associated with eczema. The details of all 234 associated diseases are listed in supplemental Table S1   The background of thousands of paediatric disorders were shown in the supplemental Table S2. F I G U R E 1 Eczema-associated paediatric disorders grouped by disease. The mean age affected by the associated diseases and log of odds ratio (OR) are plotted on the x and y axes, respectively. The size of the bubble represents the incidence of the disease in children with eczema. and allergic rhinitis, affected children at subsequent ages.

| Infection
Children with eczema were also susceptible to bacterial infection (OR   had a significantly higher OR in the eczema population, but the incidence of this condition was too low to meet the criteria.

| Ophthalmic diseases
The part of the skin most affected by eczema was the eyelids (palpe-

| Stomatological diseases
Eczema is also associated with many common oral conditions. First, eczema increased the risk of many oral infections, such as oral thrush,   These nervous conditions mostly occur in the early stage of infancy.

| Umbilical disorders
The results revealed a cluster of conditions related to the umbilical cord.

| Urogenital disorders
The vulva and scrotum were also highly affected by eczema.

| Behaviour and developmental disorders
Due to allergies to food, itchy skin and other comorbidities, many infants with eczema display some abnormal behaviours, such as

| Other disorders
The prevalence of some common symptoms in children, such as fever and jaundice, was increased in children with eczema. It appears that

Many associations between eczema and other diseases have been
reported in previous studies shown as the reference list at the end of supplemental

| Age distributions of eczema-associated diseases in paediatric patients
To further understand the distribution of the eczema-associated diseases, a subdataset comprising data from 96,460 visits by children with eczema who were also diagnosed with diseases with a high OR (>3) was used to generate Figure 2A all of these associated diseases were grouped by age and plotted in Figure 2C,D. Many relatively rare diseases were identified at the age <6 m, and many common respiratory and gastroenterology disorders contributed to the major visit count between 1 and 3 years. Since the length of data collection for this study was 7 years, theoretically if the time difference between the onset of the associated disease and eczema was more than 7 years, then no such association could be found in the data of this study.

| Rare diseases associated with eczema
To compensate for the lack of rare disease cases in this observational study, as well as to gain a more systematic understanding of eczemaassociated diseases, total 43 rare diseases were identified with eczema phenotype using phenotype query on RDmap and in which 37 rare diseases with an age of onset in antenatal, neonatal and childhood are listed in Table 3. It should be noted that this part of the disease association was not strictly analyzed statistically, but only indicates that the eczema phenotype has a relatively high frequency of occurrence in these rare diseases. The phenotypes that concomitant with eczema in rare diseases were sorted list in supplemental Table S3 based on its frequency. In addition to abnormalities of the integument and immune system, these phenotypes are associated with abnormalities of the nervous system, growth, musculature, the teeth, and the skeletal and digestive systems. Furthermore, as many rare genetic disorders coexist with joint development problems and eczema (shown in supplemental Table S3 and Figure S1), we cannot rule out the possibility that the underlying mechanism that triggers eczema affects joint development.

| DISCUSSION
Although the pathogenesis of AD involves a complex interplay of epidermal barrier dysfunction and dysregulated immune response, the increasing importance of vitamin D deficiency (OR 2.95 [2.76~3.16]) in atopic individuals has to be highlighted. 20 Vitamin D and its analogues seem to play an increasing role in the management of diseases such as AD. 21 However, the optimal dose, duration and effect of vitamin D supplementation have not been well studied. A large epidemiological study showed that eczema was strongly associated with autism and attention deficit hyperactivity disorder (ADHD). 22 However, there were negative associations in our dataset, including autism, with an OR of 0.67, and ADHD, with an OR of 0.43.
The different prevalence rates of autism and ADHD, the specific service availability, and the diagnosis age may have also contributed to these inconsistent results. Some epidemiologic studies on the association between allergic disease and epilepsy in adults and children have come to conflicting results. 23    Some of these strong correlations have never been reported in previous studies.
In summary, this is the first systematic exploration of associations between paediatric disorders and eczema using a long-term, large clinical dataset in China. More than 200 different paediatric disorders were identified, which confirmed many well-known diseases concomitant with eczema and also introduced some novel and interesting associations. These results are valuable for the development of a comprehensive approach to the management of eczema for children.

AUTHOR CONTRIBUTIONS
Haomin Li and Huiwen Zheng conceptualized and designed the study, collected data, carried out the initial analyses, drafted the initial manuscript, and reviewed and revised the manuscript. Jian Yang, Yuqing Feng, and Huilong Duan collected data and carried out the initial analyses. Lizhong Du and Qiang Shu coordinated and supervised the data collection and critically reviewed the manuscript for important intellectual content. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

ACKNOWLEDGMENTS
This study was supported by the National Natural Science Foundation of China (81871456).